Search Results (626)

Background and Objectives: Cutaneous melanoma (CM) is one of the most aggressive skin malignancies due to its rapid progression and high therapeutic resistance. Growing evidence demonstrates that the tumor microenvironment (TME)—comprising diverse immune, stromal, vascular, and epidermal cell populations alongside various cytokines and growth factors, as well as extracellular matrix (ECM) components—plays a crucial role in tumor heterogeneity, metastatic potential, and response to therapy. This review aims to synthesise current knowledge on the cellular and non-cellular constituents of the CM microenvironment and clarify their contributions to tumor progression, immune evasion, and treatment resistance. Materials and Methods: We conducted a narrative review of recent experimental, clinical, and translational studies investigating melanoma–microenvironment interactions, integrating evidence from in vitro, in vivo, and human tissue analyses. Results: Melanoma exhibits marked intra-tumoral heterogeneity driven by genetic, epigenetic, and microenvironmental influences. Cancer-associated fibroblasts, adipocytes, endothelial cells, and keratinocytes are reprogrammed by melanoma cells to promote invasion, angiogenesis, and metastasis. Immune subsets play divergent roles: neutrophils, M2 macrophages, myeloid-derived suppressor cells, and tolerogenic dendritic cells foster immune suppression, while lymphocytes—particularly CD8⁺ T cells, TFH cells, and B cells —are associated with improved outcomes but often become dysfunctional. ECM remodeling, including collagen deposition, integrin signaling, and increased matrix stiffness, actively remodels the tissue to support tumor growth and immune evasion. Hypoxia-inducible factor (HIF)-mediated signaling drives cell dedifferentiation, angiogenesis, and metabolic changes that contribute to treatment resistance. Consequently, emerging therapeutic strategies are moving beyond targeting tumor cells alone to focus on modulating TME components, counteracting immunosuppression, hypoxia, metabolic reprogramming, and extracellular vesicle signaling. Conclusions: The TME profoundly modulates tumor behavior and therapeutic response. A deeper understanding of the reciprocal interactions between melanoma cells and their microenvironmental components may enable the development of more effective strategies for early detection, prognosis, and personalized therapies. Full article

Mixed hepatocellular carcinoma (HCC)–neuroendocrine carcinoma (NEC) is a major type of liver mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN). Primary liver NEC, which is very rare, is mostly associated with HCC rather than pure NEC. To characterize the cancer cell heterogeneity of the HCC and NEC components, we comprehensively analyzed the protein expression of three cancer cell biological markers (TERT, Ki-67, and p53) and five differentiation markers (one hepatocyte marker and four neuroendocrine markers) via immunohistochemistry and immunofluorescence using curative resection tissues from three patients with liver MiNEN. TERT/Ki-67/p53 proteins, which are related to cell proliferation and malignancy, were independently expressed in the HCC and NEC components; Ki-67 was highly expressed among the three proteins in both cancer components, and the expression of all three markers was higher in the NEC component than in the HCC component. Despite the intracomponent and intercomponent heterogeneity, the expression signatures of the three markers were similar between the two components, potentially suggesting a common origin of mixed HCC-NEC. An in-depth exploration of intracomponent heterogeneity using differentiation markers revealed multiple intermediate phenotypes of cancer cells, i.e., HCC-like and NEC-like cells, mainly in the HCC component. Histologically NEC-like cells rather than HCC-like cells tended to have an intermediate percentage of Ki-67-positive cells, compared with NEC cells. The spatial distribution of various intermediate cancer cell phenotypes suggests that mixed HCC-NEC may involve the transdifferentiation from HCC cells to NEC cells through the dedifferentiation of HCC. Full article

Background/Objectives: Testicular germ cell tumors, particularly seminoma, represent the leading cause of cancer in men aged 15–40 years. The decision about adjuvant therapy relies on histological features with uncertain prognostic value. The Pituitary-Tumor-Transforming Gene 1 (PTTG1), which encodes the securin protein, is crucial in sister chromatid separation. Our previous in vitro studies demonstrated that PTTG1 nuclear expression promotes invasiveness, dedifferentiation, and neolymphangiogenesis in testicular seminoma. Methods: We conducted a hypothesis-generating retrospective observational study on 51 patients (aged 23–68) with testicular seminoma, with (43%) or without (57%) lymph node involvement, evaluating potential correlations between PTTG1 and currently known prognostic factors. Clinical and pathological data were collected, including lymph node involvement, recurrence, necrosis, rete testis invasion, vascular invasion, and adipose tissue invasion. An immunohistochemical scoring system assessing intranuclear PTTG1 expression was developed. Results: The PTTG1 score was related to lymph node metastasis and adipose tissue invasion. ROC curve analysis showed that the PTTG1 immunohistochemical score showed good discriminatory ability in identifying lymph node involvement (AUC = 0.939); the optimal cut-off was 4.0 (sensitivity 90.5%; specificity 57.1%), while the ROC curve for adipose tissue invasion was inadequate. Lymph node metastasis also correlated with necrosis; however, logistic regression confirmed that PTTG1 score was independently associated with nodal involvement (p = 0.002), regardless of tumor size and necrosis. Conclusions: Our findings suggest a correlation between PTTG1 expression and lymphadenopathy at diagnosis, independent of tumor size and T stage. It may reflect biological features associated with lymphatic dissemination and requires further investigation in larger prospective studies. Full article

Differentiated thyroid cancer (DTC), including papillary and follicular subtypes, is generally associated with favorable prognosis; however, a subset of patients develops recurrent, metastatic, or radioiodine-refractory diseases with limited therapeutic options. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a biologically relevant process in thyroid cancer, yet its role in differentiated disease remains incompletely defined. Unlike many other malignancies, thyroid cancer arises within an organ intrinsically shaped by iodine-dependent redox reactions required for thyroid hormone biosynthesis. This unique oxidative environment imposes selective pressure on tumor cells to adapt redox balance, lipid metabolism, and antioxidant defenses, all of which are central regulators of ferroptosis. Accumulating evidence indicates that ferroptosis susceptibility in DTC is dynamically modulated by differentiation status, oncogenic signaling, metabolic rewiring, and tumor microenvironmental interactions. Notably, progression toward radioiodine-refractory disease is accompanied by dedifferentiation and reinforcement of anti-ferroptotic programs, linking ferroptosis resistance to therapeutic failure. In this review, we synthesize recent original studies and contemporary reviews to provide a focused overview of ferroptosis in DTC, excluding anaplastic disease. We discuss thyroid-specific redox and iodine metabolism, genetic and metabolic determinants of ferroptosis sensitivity, lipid remodeling, and immune–microenvironmental interactions, and highlight translational opportunities for targeting ferroptosis in radioiodine-refractory DTC. By reframing ferroptosis as a context-dependent vulnerability rather than a universal death pathway, this review outlines a conceptual roadmap for integrating ferroptosis modulation into existing therapeutic strategies for DTC. Full article

The sodium/iodide symporter (NIS/SLC5A5) is a major determinant of radioiodine therapy efficacy in differentiated thyroid cancer (DTC). This narrative review examines the molecular mechanisms underlying NIS dysregulation and radioiodine refractoriness in DTC. Reduced NIS expression or function in radioiodine-refractory DTC is associated with multiple mechanisms, including transcriptional suppression linked to MAPK/ERK and PI3K/AKT pathway activation and disruption of thyroid differentiation programs; epigenetic silencing involving SLC5A5 regulatory regions; impaired protein trafficking and membrane localization; and post-transcriptional regulation by microRNAs such as miR-221-3p, miR-222-3p, miR-146b-3p, and miR-204-5p. Genetic alterations including BRAF V600E and TERT promoter mutations are associated with dedifferentiated tumor phenotypes and poor radioiodine response. Redifferentiation approaches using MAPK pathway inhibitors such as selumetinib and dabrafenib can restore iodine uptake in selected patients, although the overall clinical applicability of these strategies remains under evaluation. A better understanding of these mechanisms may support improved biologic stratification and more selective therapeutic decision-making in radioiodine-refractory DTC. Full article

The progressive decline in functional β-cell mass in Type 2 Diabetes (T2D) is increasingly recognized not as a simple apoptotic loss, but as a complex erosion of cellular identity termed “dedifferentiation.” Central to this phenotypic shift is the metabolo-epigenetic axis, where mitochondria act as the primary sensing hub, transducing nutrient flux into biochemical signals that govern the chromatin landscape. This review synthesizes current evidence on how mitochondrial metabolites—including Acetyl-CoA, α-ketoglutarate, and NAD+—serve as obligatory co-factors for the epigenetic machinery. We explore how chronic metabolic stress triggers a “Systemic epigenetic destabilization,” leading to the loss of lineage-specific markers and the formation of persistent “metabolic scars.” Furthermore, we discuss the clinical implications of these changes, specifically regarding the phenomenon of metabolic memory and the molecular limits of β-cell reversibility. By integrating foundational transcriptional studies with emerging epigenomic data, we propose that targeting the mitochondrial–epigenetic axis offers a strategic window for re-differentiating failing β-cells and restoring glycemic homeostasis. Full article

Cheliped regeneration in the E. sinensis is a tightly regulated physiological process, yet the molecular regulatory mechanisms underlying sexual dimorphism during regeneration remain unclear. In this study, we combined morphological observation with transcriptomic analysis to systematically investigate the regenerative stage characteristics and sex-related differences. The papilla stage 4 dpa was identified as a pivotal transitional stage, bridging initial wound healing and cellular dedifferentiation (2 dpa) with subsequent redifferentiation and morphogenesis (7 dpa). Morphological sex-based differences characterized by larger regenerating chelipeds in males became prominent by the late stage (28 dpa). Notably, the molecular foundation of sexual dimorphism was found to be established at 4 dpa, significantly preceding the emergence of phenotypic differences. This early divergence was driven by sex-dimorphic endocrine networks: males exhibited preferential expression of genes such as Fem-1c-like, Cyp2L1-like, CpAMP1A-like and Nedd4-like, while females showed enrichment in elevated aromatase activity. Weighted gene co-expression network analysis (WGCNA) identified the Hox gene Antp as a core hub regulator, exhibiting high co-expression with key epidermal-related genes such as Cht6, Cht2-like and more. Its suppressed expression at 2 dpa aligned with the requirements for dedifferentiation, whereas its peak at 4 dpa indicated a crucial role in orchestrating appendage patterning and exoskeleton assembly. RNA interference (RNAi) knockdown of Antp resulted in obscured differentiation between the propodus and carpus in both sexes and confirmed its regulatory control over downstream targets including Ubx, Bmp2-like, and CpAMP1A-like. This study suggests a putative hierarchical regulatory model in which systemic hormonal signals may integrate Antp and other sex-biased regulators to potentially facilitate structured limb regeneration. These findings offer tentative novel insights into the interplay between developmental plasticity and sex-based regulatory divergence in decapod crustaceans. Full article

Background/Introduction: Soft tissue sarcomas (STS) represent a diverse group of rare cancers that have variable responses to chemotherapy. Although tumor size is an established prognostic factor, its influence on the benefit of chemotherapy within specific histologies is not well understood. Methods: We conducted a retrospective analysis of 3890 patients with five STS subtypes using SEER data from 2000 to 2021. Patients were stratified by tumor size (<5 cm, 5–10 cm, >10 cm) and propensity score matched within each subtype-size cohort to control for confounders. Cox regression assessed the impact of chemotherapy on overall survival, with results presented as hazard ratios (HR) and 95% confidence intervals (95%-CI). Inverse probability of treatment weighting (IPTW) was used to improve selection bias. Results: Chemotherapy use in UPS demonstrated worse survival in smaller tumors <5 cm (HR = 2.65, 95%-CI = 1.19–5.92, p = 0.018) and 5–10 cm tumors (HR = 1.45, 95%-CI = 1.03–2.04, p = 0.031). In larger UPS tumors (>10 cm), a directionally protective association observed in matched analysis attenuated after inverse probability of treatment weighting (IPTW) (HR = 0.82, 95%-CI = 0.60–1.12, p = 0.211). Fibromyxosarcoma 5–10 cm tumors demonstrated worse survival with chemotherapy (matched HR = 3.74, 95%-CI = 2.30–6.10, p < 0.001), which remained consistent after IPTW (HR = 4.47, 95%-CI = 2.63–7.60, p < 0.001), along with >10 cm tumors (IPTW HR = 2.16, 95%-CI = 1.07–4.34, p = 0.031). DDLPS >10 cm tumors demonstrated a directionally harmful association (HR = 1.49, 95%-CI = 0.96–2.29, p = 0.073). Synovial sarcoma 5–10 cm tumors demonstrated a directionally protective trend that remained statistically non-significant across analyses. Conclusions: The effect of chemotherapy on survival in localized STS depends on both histologic subtype and tumor size. However, subgroup estimates with confidence intervals approaching 1.0 should be interpreted cautiously. Full article

Dedifferentiation—the acquisition of an early developmental state—is a hallmark of cancer. However, the underlying mechanisms that lead to cancer-associated dedifferentiation are not fully understood. Transposable elements (TEs) are becoming increasingly recognised as important regulators of development and disease. The recruitment of TE sequences has played an important role in placental evolution, and TE-derived genes play critical roles in placental development. Although important biological differences exist between tumours and the placenta, the placenta shares certain features with tumours, including the capacity to invade surrounding tissue and modulate the maternal immune response. In this regard, TEs have been implicated in cancer development, and are documented to contribute to oncogenesis through multiple different mechanisms. Moreover, cancers reacquire an epigenetic landscape, which is reflective of early development, and which corresponds to increased phenotypic plasticity, including facilitating the activation of early developmental genes. Many cancers can repurpose developmental genes, including TE-associated genes, which may contribute to pathways involved in invasion and metastasis. Determining whether TE activation is a consequence of broader epigenetic reprogramming or actively contributes to dedifferentiation will be important for understanding cancer biology and may facilitate improvements in cancer diagnosis and treatment. Full article

Introduction: Sarcomatoid dedifferentiation may be identified in both clear cell renal cell carcinoma (ccRCC) and non-clear cell RCC (nccRCC). Within the SEER database (2010–2021), we tested the effect of sarcomatoid dedifferentiation in first ccRCC and subsequently in nccRCC on cancer-specific mortality (CSM). Methods: Separate propensity score matching (PSM) and multivariable competing risks regression (CRR) analyses were first applied to ccRCC with vs. without sarcomatoid dedifferentiation and subsequently to nccRCC with vs. without sarcomatoid dedifferentiation. Results: Sarcomatoid dedifferentiation was present in 2496 (3.0%) of 82,146 ccRCC patients and in 501 (1.9%) of 26,584 nccRCC. In ccRCC, after 1:2 PSM, 2496 (100%) patients with sarcomatoid dedifferentiation vs. 4992 (6.2%) patients without sarcomatoid dedifferentiation were included. At 60 months, CSM was 45.7% vs. 33.6% in ccRCC patients with vs. without sarcomatoid dedifferentiation. In CRR sarcomatoid dedifferentiation independently predicted 1.6-fold higher CSM (HR 1.6, p < 0.001). In nccRCC, after 1:2 PSM 501 (100%) patients with sarcomatoid dedifferentiation vs. 1002 (3.8%) patients without sarcomatoid dedifferentiation were included. At 60 months, CSM was 41.7% vs. 28.1% in nccRCC patients with vs. without sarcomatoid dedifferentiation. In CRR sarcomatoid dedifferentiation independently predicted 2.0-fold higher CSM (HR 2.0, p < 0.001). Conclusion: Sarcomatoid dedifferentiation is invariably associated with higher CSM in both ccRCC and nccRCC. However, the detrimental effect of sarcomatoid dedifferentiation in CSM is more pronounced in nccRCC than in ccRCC. Full article

V-set and immunoglobulin domain-containing 1 (VSIG1) is a member of the immunoglobulin superfamily that has attracted increasing attention as a differentiation-associated protein in gastrointestinal neoplasia. Although initially described as a gastric-specific marker, accumulating evidence indicates that VSIG1 more accurately reflects gastric-enriched epithelial differentiation rather than strict anatomical origin. This conceptual shift has implications for phenotype-oriented tumor classification and diagnostic interpretation in the context of lineage plasticity. A structured and transparently reported literature search was conducted in PubMed/MEDLINE, Web of Science, and Scopus, covering studies published between 2000 and 2024. Eligible studies included original research and relevant reviews evaluating VSIG1 expression in normal tissues and digestive tract tumors, with emphasis on immunohistochemical patterns and clinicopathological correlations. In gastric cancer, VSIG1 expression consistently correlates with preserved glandular architecture and epithelial differentiation, whereas reduced or absent expression accompanies dedifferentiation and architectural disorganization. Outside the stomach, VSIG1 positivity is uncommon but reproducible in tumors exhibiting gastric-type or mixed differentiation, including settings of hepato-gastric phenotypic overlap. These patterns support interpretation of VSIG1 as a context-dependent indicator of lineage engagement and differentiation state rather than tumor origin or aggressiveness. Current data on independent prognostic value are limited and partially conflicting, and predictive roles remain unsupported, while functional data remain limited. Full article

Type 2 diabetes (T2D) is a pressing global health challenge, primarily driven by modern dietary and lifestyle patterns. Central to T2D progression is the dysfunction of insulin-secreting pancreatic β-cells, which critically disrupts glucose homeostasis. The progression to T2D relies on the β-cells’ inability to compensate for increasing insulin resistance. Initially, β-cells enhance the insulin output, but chronic nutrient overload, ER stress and inflammation ultimately compromise their function and survival. This review examines the molecular and cellular drivers of β-cell failure, focusing on endoplasmic reticulum stress, mitochondrial dysfunction and inflammatory pathways amid chronic metabolic stress. We also explore the loss of β-cell identity and altered interactions within the islet microenvironment. Understanding these mechanisms is essential for developing strategies to prevent β-cell dysfunction and slow T2D progression, ultimately supporting better metabolic health outcomes. Full article

Maladaptive tubular repair is a major contributor to fibrosis and chronic kidney disease (CKD), yet the molecular regulators of this process remain poorly understood. We report that the E3 ubiquitin ligases WWP1 and TRIM65 are novel regulators of tubular fibrosis. Both ligases were markedly induced in human and experimental CKD. WWP1 induction correlates with declining renal function in humans, highlighting the potential clinical relevance of WWP1. Profibrotic factor PAI-1 promotes a robust induction of WWP1 and TRIM65 in both primary human renal epithelial cells as well as cell line (HK-2). The silencing of WWP1 or TRIM65 significantly attenuated PAI-1-induced fibrotic signaling. Mechanistically, PAI-1 triggers a signaling cascade in which suppression of the regenerative BMP-7/SMAD5 pathway permits c-Myc induction, resulting in WWP1 and TRIM65 upregulation. The elevated expression of these ligases subsequently promotes epithelial dedifferentiation and fibrotic growth arrest. Restoration of BMP-7 or SMAD5 signaling disrupted this cascade and reduced fibrosis in renal tubular cells. Our study establishes a previously unrecognized PAI-1–c-Myc–WWP1/TRIM65 axis governing tubular maladaptive repair and positions WWP1 as a potentially new therapeutic target for slowing CKD progression. Full article

Type II collagen (CII), the major structural protein in the cartilage extracellular matrix, is a promising biomaterial for scaffold design in cartilage tissue engineering. In this study, high-purity CII was successfully extracted from bovine cartilage, an abundant by-product of cattle slaughter, and its amino acid composition, triple-helical conformation, and thermal stability were verified. CII was subsequently combined with silk fibroin (SF) and chitosan (CS) to fabricate three-dimensional (3D) porous scaffolds via freeze-drying. The pore structure, porosity, swelling behavior, mechanical properties and in vitro degradation characteristics were systematically evaluated. Scaffolds with favorable structural integrity, mechanical performance, and degradation rates were further evaluated biologically using human primary chondrocytes. All CII-based composite scaffolds supported chondrocyte growth and promoted early extracellular matrix deposition. Notably, the scaffold with a CII:SF:CS ratio of 7:3:1 showed the highest GAG/DNA content, accompanied by upregulated gene expression related to the cartilage phenotype (COL2A1, ACAN, and SOX9) and reduced expression of the dedifferentiation marker COL1A1, indicating improved phenotype maintenance. Overall, within the tested range, CII70 (CII:SF:CS = 7:3:1) represents a practical compromise between scaffold stability and in vitro chondrocyte-related outcomes, providing a basis for selecting CII/SF/CS formulations for cartilage tissue engineering. Full article